Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphoma, is clinically heterogeneous: 40% of patients respond well to current therapy and have prolonged survival, whereas the remainder succumb to the disease. We proposed that this variability in natural history reflects unrecognized molecular heterogeneity in the tumours. Using DNA microarrays, we have conducted a systematic characterization of gene expression in B-cell malignancies. Here we show that there is diversity in gene expression among the tumours of DLBCL patients, apparently reflecting the variation in tumour proliferation rate, host response and differentiation state of the tumour. We identified two molecularly distinct forms of DLBCL which had gene expression patterns indicative of different stages of B-cell differentiation. One type expressed genes characteristic of germinal centre B cells ('germinal centre B-like DLBCL'); the second type expressed genes normally induced during in vitro activation of peripheral blood B cells ('activated B-like DLBCL'). Patients with germinal centre B-like DLBCL had a significantly better overall survival than those with activated B-like DLBCL. The molecular classification of tumours on the basis of gene expression can thus identify previously undetected and clinically significant subtypes of cancer.

Coronavirus disease 2019 (COVID-19) was first reported in Wuhan, China, in late December 2019 (refs 1-3). Since then, COVID-19 has spread rapidly worldwide and has become a global pandemic affecting >200 countries and territories, with an unprecedented effect not only on public health, but also social and economic activities. The exponential increase in the number of patients with COVID-19 in the past 6 months has overwhelmed health-care systems in numerous countries across the world. At present, preventive vaccines and prophylactic therapies for COVID-19 are not available. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is a member of the genus Betacoronavirus like the two other coronaviruses that have caused pandemic diseases (severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV)) 1-4. As with SARS-CoV and MERS-CoV, SARS-CoV-2 causes a respiratory infection, which leads to viral pneumonia and acute respiratory distress syndrome (ARDS) in some patients 1. However, in addition to respiratory symptoms, uncontrolled SARS-CoV-2 infection can trigger a cytokine storm, whereby pro-inflammatory cytokines and chemokines such as tumour necrosis factor-α, IL-1β and IL-6 are overproduced by the immune system, resulting in multiorgan damage 5. Furthermore, COVID-19 causes coagulation abnormalities in a substantial proportion of patients, which can lead to thromboembolic events 6,7. The genomic sequence 1-3,8 and viral protein structure 9-11 of SARS-CoV-2 have been studied intensively since its emergence. To date, research shows that SARS-CoV-2 shares many biological features with SARS-CoV owing to 79.6% genomic sequence identity 1,2. In particular, both SARS-CoV and SARS-CoV-2 use the same system of cell entry, which is triggered by binding of the viral spike (S) protein to angiotensin-converting enzyme 2 (ACE2) on the surface of the host cell 4. Understanding the biological features of the virus will contribute to the development of diagnostic tests, vaccines and pharmacological therapies and can further our knowledge of tissue tropism. Early clinical data indicate that both the susceptibility to and the outcomes of COVID-19 are strongly associated with cardiovascular disease (CVD) 12-16. A high prevalence of pre-existing Acute respiratory distress syndrome (ArDs). A type of severe, acute respiratory failure characterized by bilateral pulmonary infiltrates and severe hypoxaemia that occurs as a result of illness or injury. Cytokine storm A form of severe immune reaction characterized by overproduction of cytokines and chemokines that can be triggered by a variety of factors such as infection and drugs.

The cytokine thymic stromal lymphopoietin (TSLP) has been linked to human allergic inflammatory diseases. We show here that TSLP expression was increased in the lungs of mice with antigen-induced asthma, whereas TSLP receptor-deficient mice had considerably attenuated disease. Lung-specific expression of a Tslp transgene induced airway inflammation and hyperreactivity characterized by T helper type 2 cytokines and increased immunoglobulin E. The lungs of Tslp-transgenic mice showed massive infiltration of leukocytes, goblet cell hyperplasia and subepithelial fibrosis. TSLP was capable of activating bone marrow-derived dendritic cells to upregulate costimulatory molecules and produce the T helper type 2 cell-attracting chemokine CCL17. These findings suggest that TSLP is an important factor necessary and sufficient for the initiation of allergic airway inflammation.

The maintenance of pregnancy relies on finely tuned immune adaptations. We demonstrate that these adaptations are precisely timed, reflecting an immune clock of pregnancy in women delivering at term. Using mass cytometry, the abundance and functional responses of all major immune cell subsets were quantified in serial blood samples collected throughout pregnancy. Cell signaling–based Elastic Net, a regularized regression method adapted from the elastic net algorithm, was developed to infer and prospectively validate a predictive model of interrelated immune events that accurately captures the chronology of pregnancy. Model components highlighted existing knowledge and revealed previously unreported biology, including a critical role for the interleukin-2–dependent STAT5ab signaling pathway in modulating T cell function during pregnancy. These findings unravel the precise timing of immunological events occurring during a term pregnancy and provide the analytical framework to identify immunological deviations implicated in pregnancy-related pathologies.

Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre-including this research content-immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

Geographically isolated wetlands (GIWs), those surrounded by uplands, exchange materials, energy, and organisms with other elements in hydrological and habitat networks, contributing to landscape functions, such as flow generation, nutrient and sediment retention, and biodiversity support. GIWs constitute most of the wetlands in many North American landscapes, provide a disproportionately large fraction of wetland edges where many functions are enhanced, and form complexes with other water bodies to create spatial and temporal heterogeneity in the timing, flow paths, and magnitude of network connectivity. These attributes signal a critical role for GIWs in sustaining a portfolio of landscape functions, but legal protections remain weak despite preferential loss from many landscapes. GIWs lack persistent surface water connections, but this condition does not imply the absence of hydrological, biogeochemical, and biological exchanges with nearby and downstream waters. Although hydrological and biogeochemical connectivity is often episodic or slow (e.g., via groundwater), hydrologic continuity and limited evaporative solute enrichment suggest both flow generation and solute and sediment retention. Similarly, whereas biological connectivity usually requires overland dispersal, numerous organisms, including many rare or threatened species, use both GIWs and downstream waters at different times or life stages, suggesting that GIWs are critical elements of landscape habitat mosaics. Indeed, weaker hydrologic connectivity with downstream waters and constrained biological connectivity with other landscape elements are precisely what enhances some GIW functions and enables others. Based on analysis of wetland geography and synthesis of wetland functions, we argue that sustaining landscape functions requires conserving the entire continuum of wetland connectivity, including GIWs.connectivity | navigable waters | significant nexus Understanding connectivity-patterns of matter, energy, and organism exchanges among landscape elements and across scales-is a challenge that unites the fields of ecology and hydrology (1). Connectivity enables dispersal of organisms and flows of water between landscape elements at multiple spatial and temporal scales

Chronic granulomatous disease (CGD), an immunodeficiency with recurrent pyogenic infections and granulomatous inflammation, results from loss of phagocyte superoxide production by recessive mutations in any 1 of 4 genes encoding subunits of the phagocyte NADPH oxidase. These include gp91 phox and p22 phox , which form the membrane-integrated flavocytochrome b, and cytosolic subunits p47 phox and p67 phox . A fifth subunit, p40 phox , plays an important role in phagocytosisinduced superoxide production via a phox homology (PX) domain that binds to phosphatidylinositol 3-phosphate (PtdIns(3)P). We report the first case of autosomal recessive mutations in NCF4, the gene encoding p40 phox , in a boy who presented with granulomatous colitis. His neutrophils showed a substantial defect in intracellular superoxide production during phagocytosis, whereas extracellular release of superoxide elicited by phorbol ester or formyl-methionyl-leucyl-phenylalanine (fMLF) was unaffected. Genetic analysis of NCF4 showed compound heterozygosity for a frameshift mutation with premature stop codon and a missense mutation predicting a R105Q substitution in the PX domain. Parents and a sibling were healthy heterozygous carriers. p40 phox R105Q lacked binding to PtdIns(3)P and failed to reconstitute phagocytosis-induced oxidase activity in p40 phox -deficient granulocytes, with premature loss of p40 phox R105Q from phagosomes. Thus, p40 phox binding to PtdIns(3)P is essential for phagocytosis-induced oxidant production in human neutrophils and its absence can be associated with disease. IntroductionSuperoxide production by the phagocyte NADPH oxidase during the respiratory burst is an essential component of the innate immune response. The active enzyme is assembled from a membrane-bound flavocytochrome b, a heterodimer composed of gp91 phox and p22 phox subunits, and cytosolic regulatory components p47 phox , p67 phox , p40 phox , and the Rac GTPase. 1,2 Genetic defects in the NADPH oxidase cause chronic granulomatous disease (CGD), characterized by absent or markedly reduced enzyme activity, recurrent bacterial and fungal infections, and granulomatous inflammation that can involve multiple organs, including the genitourinary and gastrointestinal tracts. 1,3 Recent retrospective studies report clinical and genetic findings on more than 900 patients. [4][5][6][7] Although there is some ethnic and regional variation, approximately two-thirds of CGD patients have recessive mutations in the X-linked CYBB gene encoding gp91 phox , and the remainder have autosomal recessive defects in CYBA, NCF1, or NCF2, encoding p22 phox , p47 phox , or p67 phox , respectively. Mutations involving p40 phox or Rac have not been reported as causes of CGD. An infant with a dominant-negative mutation in the hematopoietic-specific Rac2 GTPase was reported, with partial oxidase defects, markedly impaired leukocyte migration and adhesion, and a clinical picture that resembled leukocyte adhesion deficiency rather than CGD. 8,9 In the majority of CGD cases, the gen...

The patterns of cellular immune responses induced by live attenuated influenza vaccine (LAIV) versus those of the trivalent inactivated influenza vaccine (TIV) have not been studied extensively, especially in children. The goals of this study were to evaluate the effects of TIV and LAIV immunization on cellular immunity to live influenza A virus in children and adults and to explore factors associated with variations in responses to influenza vaccines among individuals. A gamma interferon (IFN-γ) flow cytometry assay was used to measure IFN-γ-producing (IFN-γ+) NK and T cells in peripheral blood mononuclear cell cultures stimulated with a live influenza A virus strain before and after LAIV or TIV immunization of children and adults. The mean percentages of influenza A virus-specific IFN-γ+ CD4 and CD8 T cells increased significantly after LAIV, but not TIV, immunization in children aged 5 to 9 years. No increases in the mean levels of influenza A virus-reactive IFN-γ+ T cells and NK cells were observed in adults given LAIV or TIV. TIV induced a significant increase in influenza A virus-reactive T cells in 6-month- to 4-year-old children; LAIV was not evaluated in this age group. The postvaccination changes (n-fold) in the percentages of influenza A virus-reactive IFN-γ+ T and NK cells in adults were highly variable and correlated inversely with the prevaccination percentages, in particular with that of the CD56dim NK cell subset. In conclusion, our findings identify age, type of vaccine, and prevaccination levels of immune reactivity to influenza A virus as factors significantly associated with the magnitude of cellular immune responses to influenza vaccines.